Synaptic transmission mediated by monoamines is terminated by a reuptake process that moves transmitter from the extracellular space into the cytoplasm. The major biochemical action of cocaine is to inhibit the activity of transporter proteins for noradrenaline (NA), dopamine (DA) and 5-HT. Thus cocaine acts to prolong the presence of transmitter extracellularly. These transporter proteins are concentrated at nerve terminals of monoamine cells, such that these terminals are key sites to investigate the actions of cocaine. Studies of the cell bodies of monoamine containing neurons in vitro suggest the there is continuous release of NA in the locus coeruleus, DA in the ventral tegmental area and 5-HT in the dorsal raphe. The inhibition of reuptake by cocaine increases the extracellular concentration of transmitters which activate autoreceptors that hyperpolarize these monamine cells. In contrast, there is not effect of cocaine on the membrane potential of cells in unstimulated preparations in areas innervated by these monoamine cells. Postsynaptic potentials are often used as a sensitive assay for transmitter release from presynaptic terminals. We will measure the amplitude and duration of synaptic potentials to study the modulation of transmitter release by cocaine. One aim of this proposal is to determine how cocaine modulates the release of monoamines from terminals. Cocaine prolongs monoamine-mediated synaptic potentials and also decreases the amount of monoamine released. The mechanism for the inhibition of monoamine release is not known. Each of the cell body regions previously studied receives projections from other monoamine nuclei. Using intracellular recording from cells in the brain slice preparation. The effects of cocaine will be studied in the ventral tegmental area and dorsal raphe. This study will focus on the interaction between S-HT, dopamine and cocaine in the VTA and the factors that regulate activity in the dorsal raphe. Knowledge of the actions of cocaine at terminals is critical to develop an understanding of how cocaine alters neurotransmission in the widespread projection areas of these and other monamine nuclei. Since 5-HT and opioids that inhibit GABA release from these terminals. Modulation at this synapse may be important in understanding mechanisms of drug reward and sensitization.